A large number of medical disorders are due to genetic defects that result in the expression of mutated and malfunctioning proteins or even total absence of that protein. Diseases, such as dystrophinopathies (e.g., Duchenne and Becker muscular dystrophies), sarcoglycanopathies, and laminin or collagen deficiencies, affect the body muscle mass and can be considered disorders, for which replacement of the malfunctioning or absent protein could effect treatment.
Congenital muscular dystrophy is a specific example of these genetically based disorders. It is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood (Tome et al., in Neuromuscular Disorders: Clinical and Molecular Genetics (ed., Emery), pp. 21–57 (John Wiley & Sons, West Sussex (1998)); and Miyagoe-Suzuki et al., Microsc. Res Tech. 48: 181–191 (2000)). Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the α2 chain of the main laminin isoforms expressed by muscle fibers. Muscle fiber deterioration in this disease is thought to be caused by failure to form the primary laminin scaffold, which is necessary for basement membrane structure (Colognato et al., Dev. Dyn. 218: 213–234 (2000)), and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) (Campbell, Cell 80: 675–679 (1995)) or the integrins (Mayer et al., Nature Genet. 17: 318–323 (1997)).
Laminins are cross-shaped heterotrimers of α, β, and γ chains (see FIG. 1a). The five α, three β, and three γ chains give rise to at least twelve different protein isoforms (laminin-1 to laminin-12) (Colognato (2000), supra), which differ in their tissue distribution (Patton et al, J. Cell Biol. 139: 1507–1521 (1997)). Mutations in the laminin α2 chain, which is the most predominant α chain in muscle and peripheral nerve, cause a most severe form of congenital muscular dystrophy, commonly referred to as merosin-deficient congenital muscular dystrophy (MCMD). Hallmarks of MCMD are a complete or partial loss of structured muscle basement membrane, ongoing muscle necrosis (which results in elevated levels of creatine kinase (CK) in the blood) and demyelination of peripheral nerves (Tome (1998), supra; Miyagoe-Suzuki (2000), supra). Deficiency of laminin α2 is accompanied by upregulation of the laminin α4 chain, giving rise to laminin-8 (see FIG. 1a; Patton (1997), supra; and Ringelmann, Exp. Cell Res. 246: 165–182 (1999)). This α chain, however, lacks domains important for laminin polymerization (Colognato (2000), supra) and binds only weakly to α-dystroglycan (Talts et al., J. Biol. Chem. 275: 35192–35199 (2000)), a principal receptor for the α2 chain (see FIG. 1a).
In view of the above, there is a need for the treatment of disorders based on genetic defects that result in malfunctioning proteins or the total absence of proteins. In particular, there is a need for treating congenital muscular dystrophy by compensating for the lack of the physical stability of muscle fibers and thereby restoring muscle function. The present invention provides such a treatment. This and other objects of the present invention, as well as additional inventive features, will be apparent from the detailed description provided herein.